Currently, balloon angioplasty induced vascular injury resulting in smooth muscle proliferation contributes to a restenosis rate in excess of forty percent, leading to repeat angioplasty and bypass surgery. Despite numerous basic and clinical research efforts employing antiproliferative, antiplatelet, and antiinflammatory drugs given systemically, no effective therapy has been found in humans (McBride et al., New Eng. J. Med., 318 (26):1734-1737 (1988); Liu et al., Circulation, 79 (6) :1374-1387 (1989)). Increasing the systemic dose of drugs to higher and potentially efficacious levels would also lead to increased toxicity in other organs. Clearly a need exists for a system that concentrates drugs locally without achieving significant systemic levels.
In one approach to prevent restenosis, researchers have attempted to deliver drugs locally in the vessel wall. However, the best means of local delivery has not been established, and very little is known of the pharmacokinetics of drugs within the vessel wall and the toxicology of large doses of drug on the integrity of the vessel. Kinetic studies of drugs delivered locally into the vessel wall to date have shown that elution of drug from the vessel wall is rapid, thus diminishing the effectiveness of the drug.
Drug delivery from polyurethanes has previously been demonstrated. For example, Kim showed that Biomer.TM., a hydrophobic polymer, could release prostaglandins in vitro and affect platelet aggregation despite a long period of storage (McRea and Kim, Trans. Am. Soc. Artif. Intern. Organs, 24:746-752 (1978); McRea et al., Trans. Am. Soc. Artif. Intern. Organs, 27:511-516 (1981)). He noted varying rates of release of compounds from that polymer but did not investigate these differences further. Release of heparin from intravascular catheters in quantities sufficient to decrease thrombosis on the catheter has been achieved by either covalently bonding a charged molecule to a polymer or incorporating a large nonmobile charged molecule on the surface of a polymer (Grode et al., J. Biomed. Mater. Res. Symp., 3:77 (1972); Barbucci et al., Biomaterials, 10:299-307 (1989)). This technology has been used for antibiotics but has not been expanded to the incorporation of other drugs (Henry et al., J. Thorac. Cardiov. Surg., 82:272-277 (1981)).
Recently, silicone based polymers which are capable of delivering various compounds have been implanted perivascularly, but the effect of drug was overshadowed by the inflammatory response to the polymer (Villa et al., The Restenosis Summit IV, 4:24 (1992)).
Polyvinyl alcohol based polymer beads, which are capable of delivering large quantities of heparin locally, have inhibited intimal hyperplasia when placed in the perivascular tissue in rats (Okada et al., Neurosurgery, 25:892-898 (1989)). However, clinical application for bead placement requiring surgery is limited.
Delivery of drug from a stent coating has previously been attempted. Cox incorporated methotrexate and heparin in a cellulose ester stent coating, but failed to show a reduction in restenosis when implanted in porcine coronary arteries (Cox et al., Circulation, 84 (4): II-71 (1991)). Local delivery of drug was not quantified, and it was not clear whether tissue levels were sufficient to block smooth muscle proliferation or whether tissue drug concentration was sufficient, but caused additional injury.
There is, therefore, a clear need in the art for means for the localized delivery of biologically active compounds to a subject, particularly to vascular tissue of a subject.